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The medicine that functions to maintain the redox state might to the pathological conditions of insulin resistance

维持氧化还原状态的药物可能对胰岛素抵抗的病理状况有作用

基本信息

批准号：
15590062
负责人：
ADACHI Tetsuo
金额：
$ 2.11万
依托单位：
Gifu Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Extracellular-superoxide dismutase (EC-SOD) is a secretory glycoprotein located in blood vessel walls at high levels and may be important in the antioxidant capability of vascular walls. The aim of this study was to assess plasma levels of EC-SOD and to evaluate the relationship of the EC-SOD level with insulin resistance in type 2 diabetic patients. We determined plasma EC-SOD in 122 patients and found for the first time that the EC-SOD level was strongly and positively related to adiponectin, and significantly and inversely related to fasting plasma glucose, body mass index (BMI) and homeostasis model assessment-insulin resistance index (HOMA-R). Administration of pioglitazone to 19 diabetic patients significantly increased the plasma levels of EC-SOD and adiponectin, while it decreased tumor necrosis factor-α (TNF-α). The present observations suggest that factors related to the pathogenesis of insulin resistance play an important role in the regulation of the plasma EC-SOD concentration.Expression of EC-SOD is known to be regulated by numerous substances such as cytokines and vasoactive factors. Transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptors (PPARs) are known to regulate genes associated with insulin resistance. We found that a C/EBPβ enhancer, prolactin, significantly induced the EC-SOD mRNA and protein levels in cultured fibroblast cell lines, but PPARγ ligands, pioglitazone and other thiazolidinedione agents did not. Deletion analysis of the EC-SOD promoter-luciferase construct showed that an important element responsible for prolactin is located between -242 and -178 in the promoter region of the EC-SOD gene in which a known C/EBPβ-binding site is located. Increasing the EC-SOD expression by treatment with ligands of transcription factors might be one approach to ameliorate the pathological conditions of insulin resistance.

细胞外超氧化物歧化酶（EC-SOD）是一种分泌型糖蛋白，在血管壁的高水平定位，并可能是重要的抗氧化能力的血管壁。本研究旨在探讨2型糖尿病患者血浆内皮细胞超氧化物歧化酶（EC-SOD）水平及其与胰岛素抵抗的关系。本文测定了122例糖尿病患者血浆EC-SOD水平，首次发现EC-SOD水平与脂联素呈显著正相关，与空腹血糖、体重指数（BMI）、稳态模型评价-胰岛素抵抗指数（HOMA-R）呈显著负相关。19例糖尿病患者服用吡格列酮后，血浆EC-SOD和脂联素水平显著升高，而肿瘤坏死因子-α（TNF-α）水平显著降低。本研究结果提示，胰岛素抵抗发病机制中的相关因素在血浆EC-SOD浓度的调节中起重要作用，EC-SOD的表达受多种物质如细胞因子和血管活性因子的调节。已知转录因子如CCAAT/增强子结合蛋白（C/EBP）和过氧化物酶体增殖物激活受体（PPARs）调节与胰岛素抵抗相关的基因。我们发现，C/EBPβ增强剂催乳素可显著诱导培养的成纤维细胞系中EC-SOD的mRNA和蛋白水平，而PPARγ配体、吡格列酮和其他噻唑烷二酮类药物则无此作用。对EC-SOD启动子-荧光素酶构建体的缺失分析表明，一个负责催乳素的重要元件位于EC-SOD基因启动子区的-242和-178之间，其中一个已知的C/EBPβ结合位点位于该区域。通过转录因子配体的干预，增加EC-SOD的表达，可能是改善胰岛素抵抗病理状态的途径之一。